Familial tumoral calcinosis and hyperostosis-hyperphosphatemia syndrome FTC (familial tumoral calcinosis) and HHS (hyperostosis-hyperphosphatemia syndrome) are caused by mutations in FGF23 (fibroblast growth factor 23), GALNT3 (N-acetylgalactosaminyltransferase 3), or KLOTHO. They are characterized by hyperphosphatemia, increased phosphate reabsorption, and elevated or inappropriately normal serum 1,25-dihydroxyvitamin D3 (1,25-D3);FTC is associated with calcific masses, and HHS with diaphyseal hyperostosis. We identified a new case of FTC/HHS due to a novel compound heterozygous mutation in GALNT3 and discovered new phenotypic findings. A 36-year-old woman presented with abnormal dental X-rays at age 12 and was hyperphosphatemic at 22. She underwent radiographic, biochemical and genetic testing, and medical treatment. The response in serum phosphate and FGF23 to medical treatment was detailed. Serum phosphorus was 7.3 mg/dL (normal range, 2.54.8), TmP/GFR 6.99 mg/100 mL (normal range, 2.974.45), 1,25-D3 35 pg/mL (normal range, 2267). Radiographs revealed tooth anomalies, thyroid cartilage calcification, calcific masses in vertebral spaces, calcification of the interstitial septa of the soft tissue in the lower extremities, and cortical thickening of the long bones. Her total hip Z score was 1.9. C-terminus serum FGF23 was 1,210 RU/mL (normal range, 20108), but intact FGF23 was 7.4 pg/mL (normal range, 1050). DNA sequencing determined she was a compound heterozygote for mutations in GALNT3. Treatment with niacinamide and acetazolamide decreased TmP/GFR and serum phosphate, which was paralleled by a decrease in serum C-terminus FGF23. This case broadens the spectrum of phenotypic and genotypic features of FTC/HHS and suggests treatments to decrease renal phosphate reabsorption in the setting of a low intact FGF23. Role of the calcium sensing receptor in bone Bone cells, particularly osteoblasts and osteoclasts, exhibit functional responses to calcium (Ca2+). The identification of the calcium-sensing receptor (CaR) in parathyroid glands as the master regulator of parathyroid hormone (PTH) secretion proved that cells could specifically respond to changes in divalent cation concentration. Yet, after many years of study, it remains unclear whether this receptor, which has also been identified in bone, has functional import there. Various knockout and transgenic mouse models have been developed, but conclusions about skeletal phenotypes remain elusive. Complex endocrine feedback loops involving calcium, phosphorus, vitamin D, and PTH confound efforts to isolate the effects of a single mineral, hormone, or receptor and most models fail to account for other local factors such as parathyroid hormone related protein (PTHrP). We have reviewed the relevant mouse models and evaluated the importance of CaR in chondrogenesis and osteogenesis. Based on these models, we suggest that there is, indeed, a non-redundant role for CaR in skeletal mineralization, including our experience in patients with activating CaR mutations (see below as an example). From this, we speculate that drugs that target the CaR directly either as agonists (calcimimetics) or antagonists (calcilytics), may have importance consequences for bone physiology and pathology. Autosomal dominant hypocalcemia (ADH) is an inherited form of hypoparathyroidism caused by activating mutations in the calcium-sensing receptor (CaR). Treatment with PTH(1-34) may be superior to conventional therapy but is contraindicated in children, and long-term effects on the skeleton are unknown. One of our patients is a 20-yr-old female with ADH who has been treated with PTH continuously since 6 yr and 2 mo of age. A bone biopsy was obtained for histomorphometry and quantitative backscattered electron imaging (qBEI). Her data were compared with one age-, sex-, and length of hypoparathyroidism matched control not on PTH and two sex-matched ADH controls before and after 1 yr of PTH. The patients growth was normal. Hypercalciuria and hypermagnesuria persisted despite normal or subnormal serum calcium and magnesium levels. Nephrocalcinosis, without evidence of impaired renal function, developed by 19 years of age, in spite of PTH therapy. Cancellous bone volume was dramatically elevated in the patient and in ADH controls after 1 yr of PTH. BMD distribution (BMDD) by qBEI of the patient and ADH controls was strikingly shifted toward lower mineralization compared with the non-ADH control. Moreover, the ADH controls exhibited a further reduction in mineralization after 1 yr of PTH. These findings imply a direct role for CaR in bone matrix mineralization. There were no fractures or osteosarcoma. In conclusion, long-term PTH replacement in a child with ADH was not unsafe, increased bone mass without negatively impacting mineralization, and improved serum mineral control but did not prevent nephrocalcinosis. Additionally, this may be the first direct evidence of a role for CaR in human bone.